SARS-CoV-2 Variants in Patients with Immunosuppression | NEJM


The mutational patterns that are described in these case reports have several key commonalities with the variants of concern and variants of interest that have become widespread. The variants B.1.1.7, B.1.351, and P.1 have at least three times as many mutations as the viruses that were circulating when these variants emerged. Likewise, investigators have detected 45 substitutions and deletions (including 17 in the spike protein) in B.1.617.2 as compared with B.1.1.7, the variant that was prevalent when B.1.617.2 emerged. A high percentage of these polymorphisms (>40%) are in the spike protein, which constitutes only 13% of the proteome. Because the spike protein is the prime target of the protective antibody response and mediates viral entry, a preponderance of mutations in this protein is consistent with adaptive evolution.

Spike Protein Structure and Phylogenetic Tree of SARS-CoV-2 Viruses.

Panel A shows the spike protein structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (entry 6ZGE in the Worldwide Protein Data Bank [PDB]). Domains are colored according to their role in viral entry and antibody recognition; the terminal domain that is missing in 6ZGE is shaded in gray. As shown in the graphic above the chart, the spike protein consists of two subunits, with subunit 1 (S1) (the portions in yellow, purple, blue, green, and pink) containing the receptor-binding domain (RBD), the N-terminal domain (NTD), and several other subdomains and subunit 2 (S2) (the portion in gray) mediating fusion of the virus-cell membrane. Also shown are the spike mutations that are representative of circulating variants of concern (B.1.1.7, B.1.351, P.1, and B.1.617.2) or variants of interest (B.1.427/429, B.1.525, and B.1.526), as well as patterns of mutations identified over the course of persistent infections in immunocompromised patients, as described in case reports. Representative sequences from the case reports are listed according to the first author’s name (1,2,4,8,10). Mutations in the NTD supersite are located nearby on the protein structure. Mutations are also recurring in the receptor-binding motif (RBM) and around the furin cleavage site. The symbols at the top of the columns indicate the N-linked glycosylation sites. CD denotes connector domain, CH center helix, CT cytoplasmic tail, HR1 heptad repeat 1, HR2 heptad repeat 2, SD1 subdomain 1, SD2 subdomain 2, S2′FP S2 fusion peptide, and TM transmembrane.

Panel B shows the phylogenetic tree of 1510 SARS-CoV-2 viruses detected in patients in the United Kingdom between January 2020 and February 2021. The phylogeny is embedded as a root-to-tip plot, in which the x axis represents the date of sample collection and the y axis represents the number of genomewide mutations that have occurred since the phylogeny root. The phylogeny is colored according to the clade, as listed in the Nextstrain database (an online site for the sharing of sequencing and genomic data about SARS-CoV-2). Clade 20I/501Y.V1 in this database corresponds to lineage B.1.1.7 in the Phylogenetic Assignment of Named Global Outbreak Lineages (PANGO) and is colored in orange and annotated in the figure. The branch leading to lineage B.1.1.7 is annotated with selected mutations that are present along this single branch. Lineage B.1.1.7 has a higher number of mutations than most other circulating viruses and has rapidly displaced existing genetic diversity in the United Kingdom. The phylogeny is constructed from sequence data shared to GISAID (a database of genomic information regarding influenza viruses and coronaviruses) by means of methods implemented by Nextstrain.

In addition, selection pressure is also shown by evidence of convergent evolution. Convergent mutations are seen in variants of concern and interest and in sequences obtained from immunocompromised patients, in particular deletions in the N terminal domain (NTD) (69-70del, Y144del, and 157-158del), the NTD supersite, and the receptor-binding domain (RBD) (K417N and E484K). These domains were associated with antibody escape or mutations that were probably associated with increased transmissibility (N501Y9 and P681H/R) ().10 Such convergent mutations have been reported in both immunocompetent and immunosuppressed populations.11 The selective advantage of these convergent mutational alterations is supported by the pace at which these variants, particularly B.1.1.7, displaced previously circulating viruses. The evolutionary pattern of the B.1.1.7 variant in the United Kingdom illustrates the rapid evolution of multiple mutations in the spike protein and its subsequent rapid spread throughout the populace (). The succession of new variants of concern or interest and the emergence of sublineages in these variants (i.e., variants of variants) illustrate a shifting evolutionary landscape in which new variants can rapidly become dominant, as suggested by the recent swift dissemination of B.1.617.2 that was originally identified in India.12 This variant shows a constellation of mutations that were identified in previous variants of concern or interest.

These compilations of case reports indicate the need to identify whether certain forms of immunosuppression are associated with an increased risk of such multimutational escape patterns — for instance, specific cancers or specific therapies, such as the development of B-cell aplasia related to CAR T-cell or anti-CD20 therapy, prolonged use of glucocorticoids, long-term chemotherapy, or radiotherapy. Similarly, organ transplant recipients and those with untreated or poorly controlled human immunodeficiency virus infection may also have prolonged SARS-CoV-2 infection and could constitute a reservoir of divergent escape variants that can spread in the general community. Prolonged viral replication in the context of an inadequate immune response facilitates the emergence of immune-pressure escape mutations.


Source: SARS-CoV-2 Variants in Patients with Immunosuppression | NEJM